Germline mutational landscape of non-highly penetrant Fanconi anemia genes unveiled from sequencing of 5,044 patients with solid tumor cancer.
Authors: Kevin McDonnell, Christine Hong, Joseph D. Bonner, Sidney Smith Lindsey, Ilana Solomon, Heather Hampel, Wai Park, Gregory Idos, Stacy W. Gray, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2022)

10521 Background: Nearly two dozen Fanconi anemia (FA) genes work in concert to mediate critical DNA repair steps. Previous investigations have well described germline pathogenic variation and associated solid tumor cancer predisposition in the highly penetrant (HP)-FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN). To date, understanding of pathogenic variation and cancer association among non-HP-FA genes remains incomplete. In this study we investigated the germline mutational landscape of non-HP-FA genes in patients with a personal/family history of a solid tumor. Methods: Unselected, consented patients with a personal/personal history of solid tumor cancer underwent germline testing through a sponsored program of universal access. Testing used a custom panel to detect pathogenic single nucleotide variants, short insertions/deletions and exon-level deletions/duplications of 155 cancer-predisposition genes including 15 non-HP-FA genes [ FANCA, FANCB, FANCC, FAND2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2)]. Here we summarize germline pathogenic variant frequency in non-HP-FA genes and describe the mutational landscape across solid tumors. Additionally, we report the clinical actionability (on- and off-label FDA approved drug availability and/or clinical trial eligibility) of identified variants. Results: 5044 patients consented and completed germline genetic testing. 1014/5044 (20.1%) of patients carried a pathogenic variant in a cancer predisposition gene. 116/1014 (11.4%) of germline positive patients carried a pathogenic variant in a non-HP-FA gene. Non-HP-FA genes with highest frequencies included: FANCA (28 patients), FANCM (19 patients), BRIP1 (FANCJ) (19 patents) and FANCC (14 patients). Testing identified germline non-HP-FA pathogenic variants in eighteen different tumor types. The tumor types associated with the highest percentages of associated germline non-HP-FA pathogenic variants included: squamous cell cancers (8.2%), bladder/urothelial cancer (5.0%), breast cancer (3.5%) and ovarian/fallopian tube cancers (3.5%). Moreover, 19 patients carrying a non-HP-FA germline pathogenic variant qualified for an on- or off-label FDA-approved drug; 101 patients achieved clinical trial eligibility by virtue of their non-HP-FA variant. Conclusions: Our study offers a landscape view of germline pathogenic variants in non-HP-FA genes in patients with a history of a solid tumor. Furthermore, this investigation provides a basis for further examination of associations between these germline pathogenic variants and solid tumor cancer predisposition. Finally, importantly, our work underscores the value of expanded germline non-HP-FA gene testing to optimize therapeutic and clinical trial opportunities for cancer patients.